Project Summary/Abstract PTI-125 is a novel small molecule Alzheimer?s disease (AD) therapeutic candidate with a novel target and mechanism of action. PTI-125 binds and reverses an altered conformation of the scaffolding protein filamin A (FLNA) to prevent A?42?s tight binding to and toxic signaling via the ?7-nicotinic acetylcholine receptor (?7nAChR) as well as A?42?s aberrant activation of toll-like receptor 4 (TLR4). Hence, by restoring FLNA?s native shape and blocking these two toxic cascades, PTI-125 reduces both tau hyperphosphorylation and neuroinflammation. Downstream effects include reduced neurofibrillary lesions and amyloid deposits, suggesting disease modification, and improved synaptic plasticity and function of ?7nAChR, NMDAR and insulin receptors, suggesting symptomatic improvement. We will pursue a label claim of symptomatic improvement instead of the more difficult claim of disease modification and will therefore conduct clinical studies in mild-to-moderate AD. Under a US IND, the first-in-human clinical trial showed no drug- related adverse effects (AEs) and dose proportional pharmacokinetics (PK). Our first-in- patient clinical trial in mild-to-moderate AD patients demonstrated 20-34% reductions in CSF P-tau, T-tau, neurogranin and neurofilament light chain, as well as 5-15% reductions neuroinflammatory markers. We have just initiated a 1-month blinded clinical trial to replicate these striking biomarker effects with two doses and correlate them with exploratory cognitive measures. This clinical trial has increased from 36 to 60 patients, and the current proposal requests funds associated with this increased trial size. With biomarker data replicated and potentially an effect size in cognitive measures, PTI-125 will be well positioned both for Phase 3 clinical trials and partnering efforts.